ABCMdb

ABCA4 p.Ile478Thr

Predicted by SNAP2:	A: N (53%), C: N (72%), D: D (59%), E: N (61%), F: N (72%), G: D (63%), H: N (61%), K: N (53%), L: N (93%), M: N (87%), N: N (53%), P: N (53%), Q: N (66%), R: N (53%), S: N (66%), T: N (72%), V: N (93%), W: D (59%), Y: N (61%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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Publications
[hide] ABCA4 gene screening by next-generation sequencing... Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, Tsubota K, Webster AR, Moore AT, Allikmets R, Michaelides M
ABCA4 gene screening by next-generation sequencing in a British cohort.
Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570., [PMID:23982839]

Abstract [show]
PURPOSE: We applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations. METHODS: We identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis. RESULTS: Of the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease-causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice-site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals. CONCLUSIONS: Application of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost-efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies.

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No. Sentence Comment
55 1 c.161G>A p.C54Y DC c.2297G>T p.G766V DC 2 2 c.223T>G p.C75G DC c.5088C>G p.S1696R DC 2 3 c.740A>C p.N247T DC c.1433T>C p.I478T B c.2345G>A p.W782* DC 2 4 c.768G>T Splice site DC 1 5 c.1222C>T p.R408* DC c.2568C>A p.Y856* DC 2 6 c.1804C>T p.R602W DC c.859-9T>C Splice site PDC 2 7 c.1805G>A p.R602Q DC c.5113C>T p.R1705W DC 2 8 c.1922G>C p.C641S DC 1 9 c.1957C>T p.R653C DC 1 10 c.1957C>T p.R653C DC 1 11 c.2588G>C p.G863A DC c.655A>T p.R219* DC 2 Allele 2 (p.R219*) was APEX-false-negative 12 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 13 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 14 c.2588G>C p.G863A DC 1 15 c.2588G>C p.G863A DC 1 16 c.2894A>G p.N965S DC c.3322C>T p.R1108C DC 2 Allele 2 (p.R1108C) was APEX-false-negative 17 c.3064G>A p.E1022K DC c.6729&#fe;4_&#fe;18delAGTTGGCCCTGGGGC Splice site DC 2 18 c.3064G>A p.E1022K DC 1 19 c.3208_3209insGT p.S1071fs DC c.2942C>T p.P981L DC c.6529G>A p.D2177N B 2 20 c.3208_3209insGT p.S1071fs DC c.1519G>T p.D507Y DC 2 21 c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 2 22 c.3208_3209insGT p.S1071fs DC 1 23 c.3292C>T p.R1098C DC c.3299T>A p.I1100N DC 2 24 c.3322C>T p.R1108C DC c.4978delC p.L1661* DC 2 25 c.3386G>A p.R1129H DC c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 3 Allele 2 (p.S1071fs) was APEX false-negative and allele 1 (p.R1129H) was NGS false-negative 26 c.4139C>T p.P1380L DC c.3191-1G>T Splice site DC 2 27 c.4139C>T p.P1380L DC c.3398T>C p.I1133T PDC 2 28 c.4139C>T p.P1380L DC c.4070C>A p.A1357E DC 2 29 c.4139C>T p.P1380L DC c.4773G>C Splice site DC 2 30 c.4139C>T p.P1380L DC 1 31 c.4139C>T p.P1380L DC 1 32 c.4139C>T p.P1380L DC 1 33 c.4234C>T p.Q1412* DC 1 34 c.4319T>C p.F1440S DC 1 35 c.4328G>A p.R1443H DC c.180delG p.M61fs DC 2 36 c.4469G>A p.C1490Y DC c.1726G>C p.D576H DC 2 37 c.4469G>A p.C1490Y DC 1 38 c.4537_4538insC p.Q1513fs DC c.5578C>T p.R1860W DC 2 Allele 1 (p.Q1513fs) was NGS-false-negative 39 c.4577C>T p.T1526M DC 1 T ABLE 2. Continued Pt Allele 1 Detected by APEX Allele 2 Detected by NGS Allele 3 Detected by NGS Total N of DC Variants Comments DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho. Login to comment
103 Hum Var Score (0-1) Site Wt CV Mt CV CV % Variation 3 c.180delG p.M61fs 1 35 ND IVS7 c.859-9T>C Splice site 1 5 Acc. 78.18 76.99 Possibly site broken (1.52) ND Possibly disease-causing 11 c.1433T>C p.I478T 1 1 Tol. B 0.007 No change ND Benign 11 c.1519G>T p.D507Y 1 20 Del. 0.01 POD 0.641 No change 1/13006 dbSNP (rs148234178) 12 c.1749G>C p.K583N 1 68 Del. 0.04 POD 0.893 Acc. 66.17 37.22 Site broken (43.75) 1/13006 dbSNP (rs145265791) 14 c.1982_ 1983insG p.A662fs 1 69 ND 15 c.2297G>T p.G766V 1 1 Tol. NA POD 0.557 Don. 69.18 42.34 Site broken (38.79) ND 15 c.2345G>A p.W782* 1 3 ND 16 c.2510T>C p.L837P 1 72 Tol. NA POD 0.905 No change ND 16 c.2568C>A p.Y856* 1 5 ND 18 c.2686A>G p.K896E 1 53 Tol. NA B 0.002 ND Benign 20 c.2942C>T p.P981L 1 19 Del. 0.00 POD 0.813 No change 1/13006 dbSNP (rs147826775) 20 c.2972G>T p.G991V 1 70 Del. NA PRD 0.998 Donor 64.62 91.45 New site (41.53) ND IVS20 c.3050&#fe;1G>C Splice site 1 54 Acc. 86.43 57.49 Site broken (33.49) ND IVS21 c.3191-1G>T Splice site 1 26 Acc. 94.38 65.44 WT site broken (30.67) ND 22 c.3289A>T p.R1097* 1 71 ND 22 c.3299T>A p.I1100N 1 23 Del. NA PRD 0.986 No change ND 23 c.3370G>T p.D1124Y 1 62 Del. NA PRD 0.998 No change ND 23 c.3392delC/ 3393C>G p.A1131Gfs 1 55 ND 23 c.3398T>C p.I1133T 1 27 Del. NA B 0.100 No change ND Possibly disease-causing 27 c.4070C>A p.A1357E 1 28 Del. NA PRD 0.94 Acc. 40.92 69.86 New site (&#fe;70.74) ND IVS30 c.4539&#fe;2T>G Splice site 1 56 Don. 79.18 52.35 WT site broken (33.89) ND 31 c.4552A>C p.S1518R 1 57 Del. NA POD 0.871 Acc. 76.3 47.36 Site broken (37.94) ND 31 c.4634G>A p.S1545N 2 21, 25 Tol. NA B 0.253 Acc. 80.04 51.1 Site broken (36.16) ND 5. Continued Exon/ IVS DNA Change Protein Change/ Effect N of Alleles Identified Pt SIFT Polyphen2 HSF Matrix Allele Freq. by EVS Reference Comments Pred. Tol. Index (0-1) Pred. Login to comment
117 Two variants (p.I478T and p.K896E) were predicted to be tolerated and benign. Login to comment
121 Overall, 31 of the 33 novel variants were considered disease-causing, except for only the two missense variants, p.I478T and p.K896E (Table 5). Login to comment